NO-cGMP-K+ Channels Pathways Participate in the Antihypertensive Effects of Attalea phalerata Martius ex Spreng Oil-Loaded Nanocapsules.

Attalea phalerata Martius ex Spreng is a palm tree that is widely distributed in the Central-West region of Brazil. In this study, we investigated whether the oil-loaded nanocapsules of A. phalerata (APON) have acute and long-lasting antihypertensive effects in male spontaneously hypertensive rats (SHR), as well as explored the underlying molecular mechanisms. APON was prepared using the interfacial polymer deposition method. The particle size, polydispersity index, and zeta potential were investigated using dynamic and electrophoretic light scattering. The antihypertensive effects of APON (administered at doses of 1, 3, and 10 mg/kg) were evaluated after acute intraduodenal administration and after 7 days of oral treatment. To investigate the molecular pathways involved, we used pharmacological antagonists and inhibitors that target prostaglandin/cyclic adenosine monophosphate, nitric oxide/cyclic guanosine monophosphate, and potassium channels. Both acute and prolonged administration of APON (at doses of 3 and 10 mg/kg) resulted in a significant reduction in systolic, diastolic, and mean arterial pressure. Prior treatment with a non-selective nitric oxide synthase inhibitor (Nω-nitro-L-arginine methyl ester), guanylyl cyclase inhibitor (methylene blue), or non-selective calcium-sensitive K+ channel blocker (tetraethylammonium) abolished the antihypertensive effects of APON. Our study showed that A. phalerata oil-loaded nanocapsules have a significant antihypertensive effect in SHR after both short-term and long-term (7-day) use. This effect seems to rely on the vascular endothelium function and involves the NO-cGMP-K+ channel pathway. This research suggests a new direction for future studies to definitively prove the therapeutic benefits of APON in treating cardiovascular disease.

Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment.

Curcumin, a natural polyphenolic component from Curcuma longa roots, is the main bioactive component of turmeric spice and has gained increasing interest due to its proposed anti-cancer, anti-obesity, anti-inflammatory, antioxidant, and lipid-lowering effects, in addition to its thermogenic capacity. While intake from dietary sources such as curry may be sufficient to affect the intestinal microbiome and thus may act indirectly, intact curcumin in the body may be too low (<1 microM) and not sufficient to affect signaling and gene expression, as observed in vitro with cultured cells (10-20 microM). Several strategies can be envisioned to increase curcumin levels in the body, such as decreasing its metabolism or increasing absorption through the formation of nanoparticles. However, since high curcumin levels could also lead to undesired regulatory effects on cellular signaling and gene expression, such studies may need to be carefully monitored. Here, we review the bioavailability of curcumin and to what extent increasing curcumin levels using nanoformulations may increase the bioavailability and bioactivity of curcumin and its metabolites. This enhancement could potentially amplify the disease-preventing effects of curcumin, often by leveraging its robust antioxidant properties.

Nanotechnological approaches in the treatment of schistosomiasis: an overview.

Schistosomiasis causes over 200,000 deaths annually. The current treatment option, praziquantel, presents limitations, including low bioavailability and resistance. In this context, nanoparticles have emerged as a promising option for improving schistosomiasis treatment. Several narrative reviews have been published on this topic. Unfortunately, the lack of clear methodologies presented in these reviews leads to the exclusion of many important studies without apparent justification. This integrative review aims to examine works published in this area with a precise and reproducible method. To achieve this, three databases (i.e., Pubmed, Web of Science, and Scopus) were searched from March 31, 2022, to March 31, 2023. The search results included only original research articles that used nanoparticles smaller than 1 µm in the treatment context. Additionally, a search was conducted in the references of the identified articles to retrieve works that could not be found solely using the original search formula. As a result, 65 articles that met the established criteria were identified. Inorganic and polymeric nanoparticles were the most prevalent nanosystems used. Gold was the primary material used to produce inorganic nanoparticles, while poly(lactic-co-glycolic acid) and chitosan were commonly used to produce polymeric nanoparticles. None of these identified works presented results in the clinical phase. Finally, based on our findings, the outlook appears favorable, as there is a significant diversity of new substances with schistosomicidal potential. However, financial efforts are required to advance these nanoformulations.

Acaricidal activity of synthetic spilanthol derivative against ticks of medical and veterinary importance.

The ANESPSAT, a synthetic spilanthol derivative, and its nanoformulation were evaluated against Rhipicephalus microplus and Amblyomma sculptum ticks. ANESPSAT activity was compared with spilanthol and derivatives (ANESPE and others). The compound was synthesized in a gram-scale by a 2-step process, comprising a direct ester amidation and a Horner-Wadsworth- Emmons reaction. The nanoemulsions were produced by coarse homogenization followed by high-energy ultrasonication, in which hydrodynamic diameter, polydispersity index, and zeta potential remained stable. The spilanthol-eugenol hybrid derivatives did not show significant acaricidal activity. ANESPE killed 83% of the R. microplus larvae at 30 mg.mL-1, while ANESPSAT killed 97% at 0.5 mg.mL-1, showing to be the most active compound. Spilanthol and ANESPSAT had similar high mortality rates for tick larvae, with LC50 values of 0.10 and 0.14 mg.mL-1 for R. microplus larvae, and 0.04 and 0.48 mg.mL-1 for A. sculptum larvae, respectively. The efficacy of spilanthol was lower against R. microplus engorged females when compared with ANESPSAT, which was highly effective (>98%) against R. microplus engorged females. The nanoemulsion with ANESPSAT was effective against tick females, preventing egg laying and achieving 100% efficacy at 2.5 mg.mL-1. Spilanthol had only 59% efficacy at 10 mg.mL-1. The results suggest that ANESPSAT, a natural product derivative, could be used in novel formulations for tick management that might be safer and environmentally friendly.

Evaluation of the efficacy of different concentrations of nano-capsules containing Talaromyces flavus with two forms of powder and suspension in reducing the incidence of cotton Verticillium wilt / Avaliação da eficácia de diferentes concentrações de nanocápsulas contendo Talaromyces flavus com duas formas de pó e suspensão na redução da incidência de murcha de Verticillium do algodoeiro

Previous domestic and foreign studies have shown the significant effect of Talaromyces flavus on growth inhibition of some important plant pathogens including Verticillium dahliae, Fusarium oxysporum f. sp. lycopersici and Fusarium oxysporum f. sp. cucumerinum. In Iran, it is necessary to produce new formulations of this fungus based on modern technologies given the importance of attracting companies producing biological control agents and transferring the technical knowledge of mass production of formulations of these agents to them. In the present study, based on the method presented in the Pesticide Research Department of the Iranian Plant Protection Research Institute, two types of T. flavus formulations in the form of nano-capsules containing Talaromyces flavus with two forms of powder and suspension were prepared using nanotechnology. In the next step, during the greenhouse examination, the efficiency of each of these new formulations in concentrations of one to five per thousand for soil addition method and concentration of five per thousand for seed impregnation method (six treatments for each of the two new formulations) was compared with the registered formulation of Talaromin in two methods of seed impregnation and soil addition with healthy control and infected control to control cotton Verticillium wilt disease, in the form of a randomized complete block design with 16 treatments and 5 replications. After statistical analysis of the data obtained by Duncan's Multiple Range Test by MS TAT C software, the results showed that in terms of disease severity among treatments with the previous formulation (Talaromin) with each of the methods of soil addition and seed impregnation, there was no statistically significant difference between nano-suspension with each of the concentrations of one, four and five per thousand by the soil addition method and nano-powder with each of the concentrations of two and three per thousand by soil addition method, and the mentioned treatments were included in one statistical group in terms of disease severity with healthy control.

Estudos anteriores nacionais e internacionais mostraram o efeito significativo de Talaromyces flavus na inibição do crescimento de alguns importantes patógenos de plantas, incluindo Verticillium dahliae, Fusarium oxysporum f. sp. lycopersici e Fusarium oxysporum f. sp. cucumerinum. No Irã, é necessário produzir novas formulações desse fungo com base em tecnologias modernas, dada a importância de atrair empresas produtoras de agentes de controle biológico e transferir para elas o conhecimento técnico de produção em massa das formulações desses agentes. No presente estudo, com base no método apresentado no Departamento de Pesquisa de Pesticidas, do Instituto Iraniano de Pesquisa em Proteção de Plantas, dois tipos de formulações de T. flavus, na forma de nanocápsulas contendo T. flavus com duas formas de pó e suspensão, foram preparados usando nanotecnologia. Na etapa seguinte, durante o exame em casa de vegetação, a eficiência de cada uma dessas novas formulações em concentrações de um a cinco por mil para o método de adição de solo e de cinco por mil para o método de impregnação de sementes (seis tratamentos para cada uma das duas novas formulações) foi comparada com a formulação registrada de Talaromin em dois métodos de impregnação de sementes e adição de solo com controle sadio e controle infectado para controle da murcha de Verticillium do algodoeiro, na forma de delineamento em blocos completos casualizados com 16 tratamentos e 5 repetições. Após análise estatística dos dados obtidos pelo Duncan's Multiple Range Test por meio do software MS TAT C, os resultados mostraram que, em termos de severidade da doença entre os tratamentos com a formulação anterior (Talaromin), com cada um dos métodos de adição de solo e impregnação de sementes, não houve diferença estatisticamente significativa entre a nanossuspensão com cada uma das concentrações de um, quatro e cinco por mil pelo método de adição de solo e entre o nanopó com cada uma das concentrações de dois e três por mil pelo método de adição de solo, e os tratamentos mencionados foram incluídos em um grupo estatístico em termos de gravidade da doença com controle saudável.

Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.

The Anti-Arthritic Activity of Diclofenac Lipid-Core Nanocapsules: Stereological Analysis Showing More Protection of Deep Joint Components.

Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is associated with serious adverse effects, even in regular-dose regimens. Drug delivery systems can overcome this issue by reducing adverse effects and optimizing their efficacy. This study evaluated the activity of lipid-core nanocapsules loaded with diclofenac (DIC-LNCs) in an experimental model of adjuvant-induced arthritis. The diclofenac nanoformulation was obtained via self-assembly. A stereological analysis approach was applied for the morphological quantification of the volume, density, and cellular profile count of the metatarsophalangeal joints of rats. Proinflammatory cytokines and biochemical profiles were also obtained. Our results showed that the diclofenac nanocapsule DIC-LNCs were able to reduce arthritis compared with the control group and the DIC group. DIC-LNCs efficiently reduced proinflammatory cytokines, C-reactive protein, and xanthine oxidase levels. Additionally, DIC-LNCs reduced the loss of synoviocytes and chondrocytes compared with the DIC (p < 0.05) and control groups (p < 0.05). These data suggest that DIC-LNCs have anti-arthritic activity and preserve joint components, making them promising for clinical use.

Challenges and advances in antimicrobial peptide development.

Microbial resistance is a major concern for public health worldwide, mainly because of the inappropriate use of antimicrobials. In this scenario, antimicrobial peptides (AMPs) have emerged as a potential therapeutic alternative means by which to control infectious diseases, because of their broad spectrum of action. However, some challenges can make their clinical application problematic, including metabolic instability and toxicity. Here, we provide a clear description of AMPs as promising molecules for the development of unusual antimicrobial drugs. We also describe current strategies used to overcome the main difficulties related to AMP clinical application, including different peptide designs and nanoformulation.

Drugs and nanoformulations for the management of Leishmania infection: a patent and literature review (2015-2022).

INTRODUCTION: Leishmaniasis is an important disease caused by parasites of the Leishmania. Due to the urgent need for financial incentives and research and development of new anti-Leishmania, a point that stands out is the creation of patents that comprise drugs and nanoformulations in treating the disease. AREAS COVERED: Information on individual patents and patent families containing potential drugs and nanoformulations were obtained by searching the Orbit software (QUESTEL SAS, France) using the following terms: Leishmania; treatment; nanoparticle*; drug×. The data obtained ranged from 2015 to 2022. EXPERT OPINION: Meglumine antimoniate is a pentavalent antimonial widely used in the classic treatment of leishmaniasis. It is part of the classic treatment recommended by WHO, being the first-choice drug globally about 75 years ago. Thus, the need to introduce new anti-Leishmania therapies into clinical medicine is evident since cases of resistance to monotherapy and multitherapy have increased greatly. Associated with this, the search for patents that are good candidates in treating this disease assues interest in investments of financial resources and raises a ray of hope for safe, effective, and low-cost therapies to become licensed for the treatment of leishmaniasis.

Nanotechnology Promoting the Development of Products from the Biodiversity of the Asteraceae Family.

Biodiversity is a hallmark of the Asteraceae family. Several species are known for their pharmacological potential. The search for new substances has permeated the chemistry of natural products for years. However, the development of a final product is still a challenge. Plant extracts have physicochemical characteristics that sometimes hinder administration, requiring a formulation. In this context, nanotechnology emerges as a tool to improve the pharmacokinetic parameters of several pharmacologically active substances. Nanoemulsions, liposomes, and nanoparticles are used to carry the active ingredients and thus improve therapeutic action, especially for substances with solubility and absorption problems. This paper aimed at compiling all the studies that used nanotechnology to develop formulations from species of the Asteraceae family from 2010 to 2021 in a literature review. The search showed that nanoemulsions are the most developed formulation associated with essential oils. The use of nanotechnology promoted an improvement in the pharmacokinetic parameters of active substances.

Naringin: Nanotechnological Strategies for Potential Pharmaceutical Applications.

Polyphenols comprise a number of natural substances, such as flavonoids, that show interesting biological effects. Among these substances is naringin, a naturally occurring flavanone glycoside found in citrus fruits and Chinese medicinal herbs. Several studies have shown that naringin has numerous biological properties, including cardioprotective, cholesterol-lowering, anti-Alzheimer's, nephroprotective, antiageing, antihyperglycemic, antiosteoporotic and gastroprotective, anti-inflammatory, antioxidant, antiapoptotic, anticancer and antiulcer effects. Despite its multiple benefits, the clinical application of naringin is severely restricted due to its susceptibility to oxidation, poor water solubility, and dissolution rate. In addition, naringin shows instability at acidic pH, is enzymatically metabolized by ß-glycosidase in the stomach and is degraded in the bloodstream when administered intravenously. These limitations, however, have been overcome thanks to the development of naringin nanoformulations. This review summarizes recent research carried out on strategies designed to improve naringin's bioactivity for potential therapeutic applications.

In vitro antibacterial activity of green tea-loaded chitosan nanoparticles on caries-related microorganisms and dentin after Er:YAG laser caries removal.

This study aimed to determine the inhibitory effects of green tea (Gt), EGCG, and nanoformulations containing chitosan (Nchi) and chitosan+green tea (Nchi+Gt) against Streptococcus mutans and Lactobacillus casei. In addition, the antibacterial effect of nanoformulations was evaluated directly on dentin after the selective removal of carious lesion. At first, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against S. mutans and L. casei isolates were investigated. In parallel, dentin specimens were exposed to S. mutans to induce carious lesions. Soft dentin was selectively removed by Er:YAG laser (n=33) or bur (n=33). Remaining dentin was biomodified with Nchi (n=11) or Gt+Nchi (n=11). Control group (n=11) did not receive any treatment. Dentin scraps were collected at three time points. Microbiological analyses were conducted and evaluated by agar plate counts. Gt at 1:32 dilution inhibited S. mutans growth while 1:16 was efficient against L. casei. EGCG at 1:4 dilution completely inhibited S. mutans and L. casei growth. Independently of the association with Gt, Nchi completely inhibited S. mutans at 1:4 dilution. For L. casei, different concentrations of Nchi (1:32) and Nchi+Gt (1:8) were required to inhibit cell growth. After selective carious removal, viability of S. mutans decreased (p<0.001), without difference between bur and Er:YAG laser (p>0.05). Treatment with Nchi and Nchi+Gt did not influence the microbial load of S. mutans on dentin (p>0.05). Although variations in concentrations were noticed, all compounds showed antibacterial activity against S. mutans and L. casei. Both bur and Er:YAG laser have effectively removed soft dentin and reduced S. mutans counts. Nanoformulations did not promote any additional antibacterial effect in the remaining dentin.

Development and biological evaluation of nanoencapsulated-based pyrethroids with synergists for resistance management of two soybean pests: insights for new insecticide formulations.

BACKGROUND: Chemical control is commonly used against Euschistus heros (F.) and Chrysodeixis includens (Walker) in soybean fields in South America. However, previous studies reported that these pests have reduced susceptibility to pyrethroids in Brazil. On this basis, we developed and evaluated nanoencapsulated-based bifenthrin (BFT) and λ-cyhalothrin (LAM) with the synergists piperonyl butoxide (PBO) and diethyl maleate (DEM) for insect resistance management (IRM). RESULTS: Nanoformulations of BFT and LAM with PBO and DEM presented good physical-chemical characteristics and were stable. The spherical morphology of all systems and the encapsulation efficiency in nanostructured lipid carriers did not change when synergists were added. Nanoencapsulated BFT with DEM applied topically increased the susceptibility of E. heros to BFT by 3.50-fold. Similarly, nanoencapsulated BFT and LAM with PBO in diet-overlay bioassays increased the susceptibility of C. includens to both chemicals by up to 2.16-fold. Nanoencapsulated BFT and LAM with synergists also improve control efficacy of both species, causing higher mortality than commercial products containing these chemistries. CONCLUSIONS: It is possible to develop nanoencapsulated-based formulations of BFT and LAM with PBO or DEM, and these nanoformulations have the potential to improve control of E. heros and C. includens with recognized low susceptibility to pyrethroids. This study provides updates for designing new insecticide formulations for IRM. © 2022 Society of Chemical Industry.

Recent approaches in nanocarrier-based therapies for neglected tropical diseases.

Neglected tropical diseases (NTDs) remain major public health problems in developing countries. Reducing the burden of NTDs requires sustained collaborative drug discovery efforts to achieve the goals of the new NTDs roadmap launched by the World Health Organization. Oral drugs are the most convenient choice and usually the safest and least expensive. However, the oral use of some drugs for NTDs treatment has many drawbacks, including toxicity, adverse reactions, drug resistance, drug low solubility, and bioavailability. Since there is an imperative need for novel and more effective drugs to treat the various NTDs, in recent years, several compound-loaded nanoparticles have been prepared with the objective of evaluating their application as an oral drug delivery system for the treatment of NTDs. This review focuses on the various types of nanoparticle drug delivery systems that have been recently used against the major NTDs caused by parasites such as leishmaniasis, Chagas disease, and schistosomiasis. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

Availability of Metribuzin-Loaded Polymeric Nanoparticles in Different Soil Systems: An Important Study on the Development of Safe Nanoherbicides.

Nanoformulations have been used to improve the delivery of fertilizers, pesticides, and growth regulators, with a focus on more sustainable agriculture. Nanoherbicide research has focused on efficiency gains through targeted delivery and environmental risk reduction. However, research on the behavior and safety of the application of these formulations in cropping systems is still limited. Organic matter contained in cropping systems can change the dynamics of herbicide−soil interactions in the presence of nanoformulations. The aim of this study was to use classical protocols from regulatory studies to understand the retention and mobility dynamics of a metribuzin nanoformulation, compared to a conventional formulation. We used different soil systems and soil with added fresh organic material. The batch method was used for sorption−desorption studies and soil thin layer chromatography for mobility studies, both by radiometric techniques. Sorption parameters for both formulations showed that retention is a reversible process in all soil systems (H~1.0). In deep soil with added fresh organic material, nanoformulation was more sorbed (14.61 ± 1.41%) than commercial formulation (9.72 ± 1.81%) (p < 0.05). However, even with the presence of straw as a physical barrier, metribuzin in nano and conventional formulations was mobile in the soil, indicating that the straw can act as a barrier to reduce herbicide mobility but is not impeditive to herbicide availability in the soil. Our results suggest that environmental safety depends on organic material maintenance in the soil system. The availability can be essential for weed control, associated with nanoformulation efficiency, in relation to the conventional formulation.

Inhalable Mannosylated Rifampicin-Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy.

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)-curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy.

Recent trends in praziquantel nanoformulations for helminthiasis treatment.

INTRODUCTION: Infections caused by parasitic flatworms impose a considerable worldwide health burden. Recently, World Health Organization launched its roadmap for neglected diseases for the period 2021 to 2030 and oral treatment with praziquantel (PZQ) in tablet form is the main drug therapy for combating these diseases, but its use is limited by many drawbacks, including the high therapeutic dose due to the drug's low solubility and bioavailability. Among the strategies to improve PZQ performance, the use of drug nanocarriers has been cited as an interesting approach to overcome these pharmacological issues. AREAS COVERED: This review focuses on the various types of nanomaterials (polymeric, lipidic, inorganic nanoparticles, and nanocrystals) which have been recently used to improve PZQ therapy. In addition, recent advances in PZQ nanoformulations, developed to overcome the barriers of the conventional drug are described. EXPERT OPINION: Considering the poor rate of discovery in the anthelmintic segment observed in recent decades, the effective management of existing drugs has become essential. The application of new strategies based on nanotechnology can extend the useful life of PZQ in new and more effective formulations. Pharmaceutical nanotechnology can solve the pharmacokinetic challenges characteristic of PZQ and improve its solubility and bioavailability.

scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression.

Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in Ldlr -/- mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages in vitro by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of IL1B and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing Ldlr -/- mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.

New nanotechnological formulation based on amiodarone-loaded lipid core nanocapsules displays anticryptococcal effect.

Cryptococcus neoformans is the etiological agent of cryptococcal meningoencephalitis. The recommended available treatment has low efficiency, with high toxicity and resistance as recurrent problems. In the search of new treatment protocols, the proposal of new pharmacological approaches is considered an innovative strategy, mainly nanotechnological systems considering fungal diseases. The antiarrhythmic drug amiodarone has demonstrated antifungal activity against a range of fungi, including C. neoformans. Here, considering the importance of calcium storage mediated by transporters on cryptococcal virulence, we evaluated the use of the calcium channel blocker amiodarone as an alternative therapy for cryptococcosis. C. neoformans displayed high sensitivity to amiodarone, which was also synergistic with fluconazole. Amiodarone treatment influenced some virulence factors, interrupting the calcium-calcineurin signaling pathway. Experiments with murine cryptococcosis models revealed that amiodarone treatment increased the fungal burden in the lungs, while its combination with fluconazole did not improve treatment compared to fluconazole alone. In addition, we have developed different innovative nanotechnological formulations, one of which combining two drugs with different mechanisms of action. Lipid-core nanocapsules (LNC) loaded with amiodarone (LNCAMD), fluconazole (LNCFLU) and both (LNCAMD+FLU) were produced to achieve a better efficacy in vivo. In an intranasal model of treatment, all the LNC formulations had an antifungal effect. In an intraperitoneal treatment, LNCAMD showed an enhanced anticryptococcal effect compared to the free drug, whereas LNCFLU or LNCAMD+FLU displayed no differences from the free drugs. In this way, nanotechnology using amiodarone formulations could be an effective therapy for cryptococcal infections.